The impact of BMI on breast cancer – an updated systematic review and meta-analysis

Background: Breast cancer is the most frequent form of cancer in women all over the world. It is the main cause of cancer death and the most often diagnosed cancer in women in 140 of the world’s 184 countries. The link between breast cancer risk and body mass index (BMI) has gotten increasing attention in recent years, although the results are still debatable. Therefore, the current systematic review and meta-analysis evaluate the impact of BMI on breast cancer. Methods: The current study was carried out as a systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched Cochrane, Google Scholar, PubMed, EMBASE and Scopus databases to identify eligible articles impact of BMI on breast cancer with the appropriate Medical Subject Headings (MeSH). The Newcastle–Ottawa checklist was used for the risk of assessment for the included studies. Meta-analysis was performed using Review Manager 5.3 software. Results: Forty-six studies were included in the current review, which met the selection criteria of the current review. Among included 46 studies in this review, 50% (n = 23) of the studies found the HER2 type of breast cancer followed by triple-negative and HR-positive. The obesity was significantly higher in the case group compared with the control group (P < .001). Heterogeneity between the 14 studies is medium (I2 = 72%). In this review, there was no significant relation between overweight and breast cancer in women (P > .05). Heterogenecity between the 14 studies is medium (I2 = 89%). However, after removing the publication bias a significant relation between overweightness and breast cancer in women (P = .0005) was observed. Conclusion: Obese breast cancer patients are a specific type of patient. They are more likely to develop cancer. Their need to surgery and radiation may cause greater difficulties. Obesity and overweight in women greatly increase the risk of breast cancer, according to the findings of the current meta-analysis. To confirm these findings and understand the pathogenic pathways, more research is required.


Introduction
Cancer is one of the world's major causes of death.The most frequent cancer among women is breast cancer and is one of the most important causes of death. [1,2]In 2012, the International Agency for Research on Cancer reported 1.7 million breast cancer new cases, with 6.3 million new patients diagnosed in the previous 5 years. [3]Every year, almost 1.5 million women worldwide are diagnosed with breast cancer. [4]Breast cancer is a type of metastatic cancer that can spread to other parts of the body, including the bones, lungs, liver, and brain, making it uncurable.A good prognosis and a high survival percentage can be achieved if the cancer is detected early. [5]The higher incidence of breast cancer in epidemiological studies among a group of women actively involved in social and professional life highlights the need for multidirectional investigations to identify risk factors linked to the development of this form of cancer. [6]Breast cancer may be caused by a number of environmental, genetic, and lifestyle factors.Alcohol consumption, obesity, lack of physical activity, and overweight has been linked to 21% of all breast cancer deaths worldwide. [7]besity, defined as a body mass index more than 30, is a chronic condition with a rising global prevalence that contributes to major health problems in most countries. [8]Around 40% of the world's female population is overweight (BMI of 25 kg/ m 2 ), according to the World Health Organization, and 15% is obese (BMI of 30 kg/m 2 ).These numbers continue to increase. [9]verweight, lack of physical activity, and obesity have been identified as the major risk factors in high and middle-income nations, accounting for 18%. [3]Multiple research relates it to the fact that adipocytes cause chronic inflammation in obesity leading to a rise in the systemic levels of cytokines as interleukin 6 and tumor necrosis factor. [10]Obesity is a known risk factor for metabolic syndrome, type 2 diabetes, and heart attacks [11] ; the latter is still the leading cause of death in women with early-stage breast cancer. [12]Obesity's strong impacts on breast cancer are caused by a variety of factors.Moreover, high BMI level is associated with a risk of several cancers, as well as an elevated cancer mortality. [13]Obesity is widely recognized as a poor prognostic factor for breast cancer, despite being shown as a risk factor. [14,15]With increasing BMI, the incidence of HR-positive breast cancer rose and HR-negative did not change.While the false-negative rate was similar over a wide range of BMIs, obese women had more cancers found on screening and at a later stage. [16]In a review by Zahmatkesh et al, [3] estimate the odds ratio of obesity and overweight as risk factors for breast cancer.Obesity, as well as overweight, was shown to have a strong link to the breast cancer risk.Recently, Harborg et al, [17] have evaluated the correlation between obesity and the outcome in triple-negative breast cancer (TNBC) patients.According to the review findings, being overweight is linked to a shorter disease-free and overall survival in TNBC patients.However, the relationship between BMI and the risk of breast cancer has received much interest, but the findings are still up for discussion. [18,19]Therefore, the current systematic review and meta-analysis evaluating the impact of BMI on breast cancer is lead.

Study design
The PRISMA guidelines was followed to conducting this systematic review and meta-analysis. [20]

Search strategy
We conducted a manual and electronic search and identified literature published up to November 30, 2021.Literature searches were carried out on databases such as Cochrane, Google Scholar, PubMed, EMBASE and Scopus with the appropriate MeSH and phrases.Different types of keywords were used for the search strategies such as "body mass index," OR "BMI," OR "obesity," OR "overweight," OR "weight," OR "adiposity" OR "weight change" AND "Cancer, breast," OR "breast cancer," OR "breast carcinoma" OR Carcinoma, human mammary OR human mammary neoplasm.The bibliographic sources of the selected articles were also screened.

Inclusion and exclusion criteria
All the published studies that report the impact of BMI on breast cancer, calculating BMI at the start and then monitoring the incidence of breast cancer during follow-up, original research articles, articles published in English were included in this review.Only studies having 95% confidence intervals (CI) on odds ratios (OR) among newly diagnosed or histopathologically confirmed breast cancer patients who had not previously had radiation, surgery, or chemotherapy were included.
Studies that evaluated other than breast cancer, assessing the impact of other comorbidities in breast cancer patients other than BMI, recurrences risk estimates of breast cancer, gray literature, including presented abstracts, letters to the editors, commentaries, systematic review, narrative reviews or meta-analysis articles and unavailability of the full text of the article were excluded from the current review.

Article screening
Relevant articles were chosen for full-text screening after applying the eligibility criteria.Two authors have independently performed articles screening process and eligibility assessment.In case of some contradictions between the authors, the decision was made by an unbiased third party.The articles were initially screened based on their title, followed by the article's abstract.The case title and abstract of the articles were irrelevant to the present investigation; these were excluded from the secondary screening.

Data extraction
The followed data was extracted from the selected articles, including the first author's name, country, study design, sample size, age, type of breast cancer, height, weight, stages, test methods, menopausal status, treatment and follow-up duration were extracted from the selected article.

Risk of bias assessment
Two reviewers independently assessed the quality assessment for the selected studies using Newcastle-Ottawa checklist.A discussion with the third reviewer solved divergences.The following are some of the Newcastle-Ottawa checklist criteria that will be used to assess study quality: Methods: (setting, participants, variables, data sources/measurement, bias), Results: (main results), Discussion: (limitations, generalizability).The total score ranged from 0 to 9, while scores less than 3, less than 6 and between 7 and 9 will be considered as low, moderate and high-quality studies, respectively.

Statistical analysis
Review Manager 5.3 was used to conduct the meta-analysis (The Cochrane Collaboration, 2014).The combined effect size was calculated using a meta-analysis with a 95% CI.Pooled OR and 95% CI estimates was computed using randomeffects modeling and forest plots were used to display the results.Random effects modeling was used because, regardless of the level of statistical heterogeneity.The I 2 statistic was used to analyze the clinical heterogeneity of included studies using the Cochran Q test.Significant heterogeneity was defined as I 2 larger than 50%.To identify the source of heterogeneity, sensitivity analysis was performed by assessing the influence of different study features such as sample size, publication year, and menopausal status.Visual inspection of a funnel plot was used to determine publication bias.The statistical tests were two-sided, and P < .05 was used to determine statistical significance.

Ethical considerations
No ethical approval or patient consent was required in this review because all analyses was based on already published studies.To prevent ethical issues with regards to plagiarism and copyrights, the findings from the selected articles were duly paraphrased along with acknowledging the work of the authors via the addition of references.

Eligible studies
A total of 1711 articles were found in searched databases, including Cochrane, Google Scholar, PubMed, EMBASE and Scopus, of which 1112 were initially eliminated owing to repetition and irrelevance.After analyzing the titles and abstracts at the first screening level, 490 articles were further removed.For full-text evaluations, a total of 109 potential relevant articles were chosen, of which 63 articles were further excluded as studies that reported other cancers and disease (n = 39), studies that related to other comorbidities (n = 14) and review, systematic review and meta-analysis articles (n = 10).Finally, 46 studies that met the criteria for inclusion in the systematic review, as detailed in the PRISMA flow chart (Fig. 1), were included in this review.

Risk of bias
The Newcastle-Ottawa checklist was used to risk of bias assessment of the included studies.The risk of bias assessment for each study is shown in Table 2.Among the assessed 46 studies, 33 studies have a "moderate risk," whereas the remaining 13 studies have a "low risk."rance Retrospective cohort study Abubakar et al, [23]  Krasniqi et al, [24] Italy Observational study N = 709/Female Median = 54 (26-87) HER2 + metastatic breast cancer (mBC) NR NR NR 5 Gondo et al, [25] Japan retrospective cohort study Cho et al, [27] Korea Observational study N = 5668/Female Median = 48 and 52 HR+/Her2-NR NR NR 8 Al Jarroudi et al, m [28] North africa Engmann et al, [29]

Clinical characteristics
Among included in this review, 50% (n = 23) of the studies found the HER2 type of breast cancer followed by triple-negative and HR-positive.Most of the included studies were included both premenopausal and postmenopausal status.The follow-up duration was ranging from 6 months to 16.2 years.The findings of the included studies were demonstrated that the higher BMI is associated with greater breast cancer risk.

Impact of BMI on breast cancer
The meta-analysis comprised 16 case-control studies in total.Among the selected 16 studies, the BMI data was calculated into 2 groups, including overweight (BMI > 25 to < 30 kg/ m 2 ) and Obese (BMI ≥ 30).The OR was used in selected studies to examine the effect of a high BMI (overweightness and obesity) on breast cancer.The random effects approach was used to analyses studies, which revealed that they were heterogeneous.

Obesity
Fourteen studies report the Meta analysis between case and control group for obesity (BMI ≥ 30 kg/m 2 ).The study reported a significant difference between the case and control groups (P < .001).The study reported that obesity was significantly higher in the case group compared with the control group (P < .001).Heterogeneity between the 14 studies is medium (I 2 = 72%).Test for overall effect: Z = 3.55 (P = .0004)(OR = 1.37 CI: 1.15-1.63)(Table 3, Figs. 2 and 3).

Discussion
Obesity is a worldwide epidemic, with 69% of people in the United States and 38% worldwide being overweight or obese. [67]besity is linked to changes in whole-body physiology and hormonal environment, which can lead to a variety of diseases.Obesity has been linked to a poor prognosis in a variety of cancers, including breast cancer. [68]BMI has been used as a marker of generalized obesity in the majority of research and metaanalyses available and found an elevated risk of breast cancer in obese or overweight women of all ethnic groups during the postmenopausal period. [51,68]In this study, we review the evidence of the relationship between BMI and breast cancer, with an emphasis on breast cancer prognosis.In this review, 46 included studies comprising 2,95,260 patients were included to explore the relationship between breast cancer risk and BMI.Obesity was significantly higher in the case group compared to the control group (P < .001),according to the 16 case-control studies included in the meta-analysis.Heterogeneity between the 14 studies is medium (I 2 = 72%).After removing the publication bias a significant difference between the case group and control group (P < .001)for obesity was observed.A study examining breast cancer risk factors in the Eastern Mediterranean region (EMRO) by Namiranian et al showed that being obesity increases the breast cancer incidence, and this association was statistically significant, [69] confirming the current findings.Furthermore, Jee et al [70] discovered that a higher BMI might raise the incidence of breast cancer in the Korean population.In this review, there was no significant relation between overweightness and breast cancer in women (P > .05).Heterogeneity between the 14 studies is medium (I 2 = 89%).However, after removing the publication bias a significant relation between overweightness and breast cancer in women (P = .0005)was observed.Similarly, in a review by Zahmatkesh et al, [3] estimate the odds ratio of obesity and overweight as risk factors for breast cancer.Obesity was discovered to have a strong link to the breast cancer risk (OR = 1.81, 95% CI = 1.24-2.64).There was also a link found between being overweight and the risk of breast cancer (OR = 1.46, 95% CI = 1.13-1.89).
Although the specific mechanism behind the association between BMI and breast cancer risk is uncertain, numerous possibilities have been proposed.The higher level of estrogen produced by the aromatization of and rostenedione in the larger fat reserves of postmenopausal women was assumed to be the reason of the positive relationship between BMI and breast cancer risk. [7]The protective impact of greater weight in the early premenopausal years, it is linked to longer anovulatory cycles and decreased progesterone and estrogen levels, is likely to have contributed to the negative link between higher BMI and breast cancer risk in premenopausal women.However, more investigations of carcinogenic pathways will be required to confirm these predictions.The evaluation of study quality, the extensive literature search process, and the large number of studies included are all strengths of our review.The investigations were conducted in a range of places throughout the world, with a diverse breast population adding to the data' generalizability.However, the present review has some limitations.Firstly, we used subgroup analysis to find the major source of heterogeneity after observing it across studies.Secondly, the meta-analysis included only case-control studies.Thirdly, our meta-analysis' findings were confined to Iran, Thailand, Malaysia, and Singapore, and may not be applicable to other locations such as Africa or the United States.Despite these limitations, this updated review provides an evidence-based report on the impact of BMI on breast cancer demonstrated by pooled effect of different studies using rigours methodology.

Conclusion
Obese women with breast cancer are a specific type of patient.Women with higher BMI are more likely to develop cancer as well as increased surgery and radiation difficulties.Obesity and overweight in women greatly increase the risk of breast cancer, according to the findings of the current meta-analysis.More research is needed to confirm these findings and understand the pathogenic pathways.et al, [59] Y Results for the Categorical analysis of the association between BMI and breast cancer after removing the studies which lies outside the funnel.

Figure 2 .
Figure 2. Funnel plot of odds ratio estimates of breast cancer by obesity.

Figure 3 .
Figure 3. Forest plot of odds ratio estimates of breast cancer by obesity.

Figure 4 .
Figure 4. Funnel plot of odds ratio estimates of breast cancer by obesity after removing studies which lies outside the funnel.

Figure 5 .Figure 6 .
Figure 5. forest plot of odds ratio estimates of breast cancer by obesity after removing studies which lies outside the funnel.

Figure 7 .
Figure 7. Forest plot of odds ratio estimates of breast cancer by overweight.

Figure 8 .Figure 9 .
Figure 8. Funnel plot of odds ratio estimates of breast cancer by overweight after removing studies which lies outside the funnel.

Table 1
Characteristics of included studies.

Table 2
Risk of bias assessment the included studies.